Alzheimer's disease is a progressive neurodegenerative disease characterized by the deposition of amyloid β protein (Aβ), accumulation of phosphorylated tau in a nerve cell (neurofibrillary tangle), and nerve cell death. In recent years, the number of patients with Alzheimer's disease is increasing because of aging, but an effective treatment method has not been developed as yet. The therapeutic drugs for Alzheimer's disease which are currently used in the medical practice are mainly acetylcholinesterase (AchE) inhibitors. While AchE inhibitors is confirmed to provide a certain level of usefulness, since they are used with the aim of supplementing decreased acetylcholine, the treatment with AchE inhibitor is merely a symptomatic therapy. Thus, the prompt development of a basic remedy and prophylactic drug has been strongly desired.
It has been clarified that the presence of allele ε4 of apolipoprotein E (ApoE) controlling the cholesterol metabolism is a strong risk factor of Alzheimer's disease [non-patent document 1: Science, vol. 261, 921-923, 1993]. After this finding, the correlation between plural gene polymorphisms playing a role in the expression of protein controlling the cholesterol metabolism and the onset frequency of Alzheimer's disease has been shown, suggesting the correlation between the cholesterol metabolism and Alzheimer's disease [non-patent document 2: Neurobiol. Aging, vol. 24, 421-426, 2003, non-patent document 3: Mol. Psychiatry, vol. 8, 635-638, 2003]. Moreover, it has been reported that Cyp46 (same as “cholesterol 24-hydroxylase (CH24H)”), which is cholesterol oxidase specifically expressed in the brain, is a risk factor of Alzheimer's disease [non-patent document 4: Neurosci. Lett., vol. 328, pages 9-12, 2002]. Furthermore, it has also been reported that Cyp46 (CH24H) is expressed in periphery of deposited amyloid in Alzheimer's disease patients [non-patent document 5: J. Biol. Chem., vol. 279, pages 34674-34681, 2004], 24S-hydroxycholesterol (24-HC), which is a metabolite thereof, increases in the brain spinal cord fluid (CSF) of Alzheimer's disease patients [non-patent document 6: Neurosci. Lett., vol. 324, pages 83-85, 2002, non-patent document 7: Neurosci. Lett., vol. 397, pages 83-87, 2006], 24-HC induces cell death of SH-SY5Y cell, which is a human neuroblast line [non-patent document 8: Brain Res., vol. 818, pages 171-175, 1999], and rats in which 24-EC was injected into the lateral cerebral ventricle showed impaired short-term memory, which is commonly observed in Alzheimer's disease, suggesting that hippocampal neurons were damaged by 24-HC [non-patent document 9: Neuroscience, vol. 164, pages 398-403, 2009]. These findings suggest that Cyp46 (CH24H) is deeply involved in the pathology of Alzheimer's disease. Therefore, a compound that inhibits the Cyp46 (CH24H) activity (i.e., Cyp46 (CH24H) inhibitor) suppresses neuronal cell death, increase in Aβ, intracerebral inflammation and the like observed in Alzheimer's disease, by decreasing intracerebral 24-HC, and is promising as a therapeutic or prophylactic drug showing not only an improvement of symptoms but also a suppression of progression. Moreover, it has been reported that an AchE inhibitor clinically used as a therapeutic drug for Alzheimer's disease shows an improvement effect on memory disorders induced by Aβ in mouse [non-patent document 10: British Journal of Pharmacology, vol. 149, pages 998-1012, 2006]. Thus, a Cyp46 (CH24H) inhibitor showing an improvement effect for memory disorders in Aβ overexpression animal model (APP transgenic mouse, APP/PS1 double transgenic mouse, etc.) is promising as a therapeutic drug for Alzheimer's disease.
As a concept of the preclinical stage of Alzheimer's disease, a mild cognitive impairment has been proposed, and about half of those having this disorder is said to progress into the Alzheimer's disease in the future. In recent years, it has been reported that 24-HC increases not only in patients with Alzheimer's disease but also in CSF of patients with mild cognitive impairment [non-patent document 7: Neurosci. Lett., vol. 397, pages 83-87, 2006]. This finding suggests that Cyp46 (CH24H) is involved in the pathology of mild cognitive impairment, and therefore, a Cyp46 (CH24H) inhibitor is promising as a new therapeutic drug for Alzheimer's disease or a prophylactic drug for the progression into the Alzheimer's disease.
In recent years, moreover, it has been reported that 24-HC in the blood increases before expression of the symptom in an autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis which is one of the demyelination diseases in the central nervous system [non-patent document 11: J. Neurosci. Res., vol. 85, pages 1499-1505, 2007]. Multiple sclerosis is often developed in younger people of about 30 years old, and scarcely developed in the elderly of 60 years or older. It has also been reported that 24-HC in the blood increases in multiple sclerosis patients aged from 21 to 50 [non-patent document 12: Neurosci. Lett., vol. 331, pages 163-166, 2002]. These findings suggest that Cyp46 (CH24H) is involved in the pathology of multiple sclerosis, and therefore, a Cyp46 (CH24H) inhibitor is promising as a new therapeutic or prophylactic drug for multiple sclerosis.
Traumatic brain injury (also referred to as TBI in the present specification) is a condition having an extremely harmful influence on the personal health, for which no effective cure has been established. In the repair process following tissue damage by TBI, reconstruction of neuronal cell membrane and distribution of intracerebral cholesterol along with the growth of glial cell are suggested to be activated [non-patent document 13: Proc. Natl. Acad. Sci. USA, vol. 102, pages 8333-8338, 2005]. In a rat TBI model, an enhanced expression of Cyp46 (CH24H) after trauma has been reported [non-patent document 14: J. Neurotrauma, pages 1087-1098, 2008]. Moreover, it has also been reported that 24-HC is injurious to neuronal cells [non-patent document 8: Brain Res., vol. 818, pages 171-175, 1999]. Therefore, a Cyp46 (CH24H) inhibitor is promising as a new therapeutic or prophylactic drug for TBI.
As a pathological significance of 24-HC in neurodegenerative diseases, an inflammatory gene expression-enhancing action in neuronal cells has been reported [non-patent document 15: NeuroReport, vol. 16, pages 909-913, 2005]. In addition, it is suggested that an intracerebral inflammation reaction accompanied by activation of glial cell is a pathological change characteristic of neurodegenerative diseases [non-patent document 16: Glia, vol. 50, pages 427-434, 2005]. In recent years, an effectiveness of therapy by suppression of intracerebral inflammation has also been reported for neurodegenerative diseases such as Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis and the like [non-patent document 17: Mol. Neurodegeneration, vol. 4, pages 47-59, 2009]. Therefore, suppression of intracerebral inflammation via decreasing 24-HC by the inhibition of Cyp46 (CH24H) is promising as a new therapeutic or prophylactic drug for neurodegenerative diseases such as Huntington's disease, Parkinson's disease, cerebral infarction, glaucoma, amyotrophic lateral sclerosis and the like.
Glaucoma is the main cause of blindness, and is considered to be a serious social problem. However, there is no effective cure of a normal intraocular pressure type-visual field constriction, which is the major symptom of the disease. In recent years, it has been reported that gene polymorphisms of Cyp46 (CH24H) associated with high value of 24-HC in blood is related to the risk of the onset of glaucoma [non-patent document 18: Invest. Ophthalmol. Vis. Sci., vol. 50, pages 5712-5717, 2009]. Thus, a Cyp46 (CH24H) inhibitor is promising as a therapeutic or prophylactic drug for glaucoma.
Spasm is a disorder that convulsively occurs with abnormal electrical excitation of neuronal cell in the brain. Spasm is one of the characteristic clinical findings of Alzheimer's disease [Non-Patent Document 19: Epilepsia, vol. 47, pages 867-872, 2006], and the relationship between epilepsy and onset of Alzheimer's disease has been indicated [Non-Patent Document 20: Epilepsia, vol. 52, Supplement 1, pages 39-46, 2011]. It has been reported that spasm occurs with high frequency in APP/PS1 double transgenic mouse which is one of the Alzheimer's disease models due to Aβ overexpression [non-patent document 21: J. Neurosci., vol. 29, pages 3453-3462, 2012]. Furthermore, since hippocampus astrocytes induce the expression of Cyp46 (CH24H) in a kainic acid lesion rat model, which is one of the epilepsy models, the relationship between this enzyme and pathology of epilepsy has been indicated [Non-Patent Document 22: J. Neurol., vol. 65, pages 652-663, 2006]. It has been reported that a therapeutic drug for spasm, carbamazepine, shows an improving effect on short-term memory in Y-maze test in an epileptic spasm mouse model [Non-Patent Document 23: J. Neurol. Neurosurg. Psychiatry, vol. 48, pages 459-468, 1985]. Therefore, a CH24H inhibitor, which shows an improving effect on short-term memory in a model animal showing a spasm symptom, is promising as a novel therapeutic drug or prophylaxis drug for spasm, epilepsy, and the like.
Since schizophrenia shows a variety of psychological symptoms such as hallucination, delusion, excitation, manic-depressive state and the like, therapeutic drugs therefor have been developed with various approaches. In recent years, it has been pointed out that changes in the cholesterol metabolism are involved in the abnormality of neural activity seen in schizophrenia [non-patent document 24: J. Psychiatry Neurosci., vol. 36, pages 47-55, 2011]. Since cytotoxic factors such as oxidative stress also contribute to the pathology of schizophrenia, neuronal cell toxicity of 24-HC may aggravate the symptoms [non-patent document 25: Psychoneuroendocrinology, vol. 28, pages 83-96, 2003]. Therefore, a Cyp46 (CH24H) inhibitor that inhibits metabolizing cholesterol to 24-HC in the brain is promising as a therapeutic or prophylactic drug for schizophrenia.
Patent Document 1 discloses the following compound as an agent for the treatment of virus infection.
whereinZ is bond or (C1-C3)alkylene;W is selected from CH or N;A is selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C1-C6) alkoxy and the like;R1 is selected from the group consisting of hydrogen, halo, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy and the like;R2 is independently selected from the group consisting of hydroxy, oxo, (C1-C6)alkyl, (C3-C14)cycloalkyl and the like;R2′, R3, R3′ and R4′ are independently selected from hydrogen, (C1-C6) alkyl, (C3-C14) cycloalkyl and the like;R4 is selected from the group consisting of hydrogen, hydroxy, halo, nitrile, (C1-C6) alkyl, (C1-C6) alkoxy and the like; and n is an integer of 1 to 4.
Patent Documents 2 and 3 disclose the following compound having an HIF inhibitory action as an agent for the prophylaxis or treatment of inflammatory disease, cancer and the like.
whereinR1 is H, alkyl, alkenyl, alkynyl, —CN, halogen or the like,R2 is H or C1-C4 alkyl,R3 is H or —CH3,R4 is an optionally substituted phenyl or the like,R5 is H or —CH3, andR6 is H, halogen, alkyl, alkoxy, alkenyl, alkynyl or the like, provided thatR4 is not 3-alkoxy-pyridazin-5-yl,when R4 is phenyl, then the 2- and 5-positions of the phenyl ring may not be substituted with two methoxy substituents at the same time, andR3 and R5 are not at the same time H.
Patent Document 4 discloses the following compound having a PGD2 receptor antagonistic action as an agent for the prophylaxis or treatment of allergic disease and the like.
whereinRing A is an aromatic carbocycle or an aromatic heterocycle;Ring B is a nitrogen-containing non-aromatic heterocycle or a nitrogen-containing aromatic heterocycle;Ring C is an aromatic carbocycle or an aromatic heterocycle;R1 is hydroxyalkyl, carboxy, alkyloxycarbonyl or the like;each R2 is independently a halogen atom, optionally substituted alkyl or the like;R3 is a hydrogen atom, optionally substituted alkyloxy or the like;each R4 is independently a halogen atom, optionally substituted alkyl or the like;each R5 is independently a halogen atom, optionally substituted alkyl or the like;M is carbonyl or sulfonyl;Y is a single bond, alkylene which optionally contains 1 or 2 hetero atoms and is optionally substituted, or the like;L1, L2, and L3 are each independently a single bond, alkylene which optionally contains 1 or 2 hetero atoms and is optionally substituted, or the like;K is 0, 1, 2, 3 or 4;n is 0, 1 or 2; andq is 0, 1, 2 or 3
Patent Document 5 discloses the following compound as an inhibitor of BACE2, Cathepsin D and the like, which is an agent for the treatment of neurodegenerative disease (e.g., Alzheimer's disease, Down syndrome, etc.).
whereinR1 is CH (Re) C(═O)N(Ra)Rb or (CH2)kN(Rc)Rd                 wherein        k is 0, 1 or 2;        Ra and Rb are independently hydrogen or optionally substituted (C1-8)alkyl or the like,        Rc and Rd are independently hydrogen or optionally substituted (C1-8)alkyl or the like, or        Ra and Rb in combination or Rc and Rd in combination form, together with the nitrogen that they are bonded to,        optionally substituted pyrrolidinyl, 1-piperidinyl or the like; and        Re is optionally substituted (C1-8) alkyl, (C1-4)alkoxy(C1-4)alkyl or the like;R2 is hydrogen or (C1-4)alkyl;R3 is hydrogen, (C1-6) alkyl, optionally substituted (C1-6)alkylOC(═O)NH or the like;Ar is an aromatic or hetero aromatic ring, each optionally substituted by halogen, (C1-4)alkoxy, hydroxy or (C1-4)alkyl, andU and X1 are bonded to the ring at ortho- or meta-position, each other;U is a bond, —O—, CF2, CF2CF2 or the like,Rg is hydrogen, (C1-8) alkyl or (C3-7)cycloalkyl;V1 is hydrogen, andV2 is hydroxy, orV1 and V2 in combination form oxo;W is CH═CH, cycloprop-1,2-ylene or the like,X1 is CRfRf,        wherein each Rf is independently hydrogen, fluorine, optionally substituted (C1-8) alkyl, (C1-4)alkoxy(O1-4)alkyl, (C3-7)cycloalkyl or (C3-7)cycloalkyl(C1-4)alkyl group;Y is a bond, O, S(═O)2, S(═O)2NRg, N(Rg)S(═O)2 or the like,        wherein Rg is hydrogen, (C1-8)alkyl or (C3-7)cycloalkyl; andZ is O, CH2, CF2, CHF, cycloprop-1,2-ylene or a bond, the large cyclic ring contains 14, 15, 16 or 17 ring atoms.        
Patent Document 6 discloses the following compound having a CH24H inhibitory action as an agent for the treatment of neurodegenerative disease (e.g., Alzheimer's disease, mild cognitive disorder, multiple sclerosis and the like).
whereinRing Aa is an optionally substituted ring;R1a is(1) a group represented by the formula: —X1a—R6a                 wherein X1a is a C1-6 alkylene group, a C2-6 alkenylene group or a C3-6 cycloalkylene group, and R6a is an optionally substituted C6-14 aryl group, an optionally substituted C6-14 aryloxy group or an optionally substituted heterocyclic group,(2) an optionally substituted C6-14 aryl group,(3) an optionally substituted C6-14 aryloxy group, or(4) an optionally substituted heterocyclic group;R2a is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-6 cycloalkyl group or an optionally substituted hydroxy group,R3a is an optionally substituted C1-6 alkyl group, an optionally substituted C3-6 cycloalkyl group or an optionally substituted hydroxy group, orR2a and R3a in combination optionally form an oxo group, a C1-3 alkylidene group or an optionally substituted ring; andR4a and R5a are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-6 cycloalkyl group or an optionally substituted hydroxy group, orR4a and R5a in combination optionally form an oxo group, a C1-3 alkylidene group or an optionally substituted ring.        
Patent Document 7 discloses the following compound having a calcium-sensing receptor (CaSR) antagonistic action as an agent for the treatment of bone disease (e.g., osteoporosis, bone fracture and the like).
whereinRing Aa is an optionally substituted ring;R1a is
(1) a group represented by the formula: —X1a—R6a                 wherein X1a is a C1-6 alkylene group, a C2-6 alkenylene group or a C3-6 cycloalkylene group, and R6a is an optionally substituted C3-6 cycloalkyl group, an optionally substituted C3-6 cycloalkyloxy group, an optionally substituted C6-14 aryl group, an optionally substituted C6-14 aryloxy group, an optionally substituted C7-14 aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclyloxy group or optionally substituted amino group,(2) an optionally substituted C3-6 cycloalkyl group,(3) an optionally substituted C3-6 cycloalkyloxy group,(4) an optionally substituted C6-14 aryl group,(5) an optionally substituted C6-14 aryloxy group,(6) an optionally substituted C7-14 aralkyloxy group,(7) an optionally substituted heterocyclic group,(8) an optionally substituted heterocyclyloxy group, or(9) an optionally substituted amino group;R2a is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-6 cycloalkyl group or an optionally substituted hydroxy group,R3a is an optionally substituted C1-6 alkyl group, an optionally substituted C3-6 cycloalkyl group or an optionally substituted hydroxy group, orR2a and R3a in combination optionally form a C1-3 alkylidene group or an optionally substituted ring; andR4a and R5a are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-6 cycloalkyl group or an optionally substituted hydroxy group, orR4a and R5a in combination optionally form an oxo group, a C1-3 alkylidene group or an optionally substituted ring.        